Targeting glutamate in OCD: a placebo-controlled, double-blind augmentation trial of the glutamate-modulating agent riluzole in treatment-refractory OCD. Obsessive-compulsive disorder (OCD) affects approximately 2.5% of the population worldwide. About a quarter of patients have symptoms that are resistant to available medications and psychotherapeutic approaches. Many of those described as `responders'to existing treatments suffer substantial residual symptoms and lead constricted lives. New treatment approaches are urgently needed. Several lines of evidence suggest that the ubiquitous amino acid neurotransmitter glutamate may be dysregulated in the brains of patients with OCD. This leads to the hypothesis that medications that target glutamate may represent a novel treatment strategy. The glutamate-modulating medication riluzole, which has been FDA approved for over ten years for use in amyotrophic lateral sclerosis, is one such agent. Preliminary open-label data suggest that a substantial fraction of patients with profoundly treatment-resistant OCD, who suffer severe symptoms and impaired quality of life despite medication and psychological treatment, improve when riluzole is added to their regimen. Importantly, several patients with compulsive hoarding, which is notoriously refractory to current treatments, have responded to pharmacological augmentation with riluzole. These preliminary observations do not provide adequate evidence of the efficacy of riluzole in OCD to justify its general clinical use. A more rigorous, controlled trial is essential. As a step towards this end, and to explore feasibility issues essential to the design of a larger, multi-site trial, this application proposes a pilot placebo-controlled, double-blind trial of riluzole augmentation in OCD. 60 outpatients with treatment-resistant OCD on stable medication regimens will be randomized to receive either riluzole (at the standard dose of 50 mg twice daily) or placebo, following a two-week single-blind placebo lead-in phase. The primary outcome measure will be improvement in Y-BOCS;measures of depression, anxiety, quality of life, and other variables will be analyzed in secondary analyses. In exploratory analyses, we will investigate genetic and clinical variables as potential predictors of response. DNA will be collected from all patients. Exploratory analyses of candidate genes in the serotonin and glutamate systems and of specific dimensions of symptomatology may help identify predictors of treatment response. While this study is not powered to definitively identify the predictors of response to riluzole, it will allow the generation of specific hypotheses to be further explored in a larger future trial. Many patients suffer from treatment-resistant OCD. This trial is a critical step towards exploring the efficacy glutamate modulating agents such as riluzole as a new alternative to alleviate their suffering.